In this article, we’ll review data that persuaded the FDA to allow metformin to be studied in humans as the first anti-aging drug.1

Broad-Spectrum Effects

The most commonly prescribed antidiabetic drug is metformin. It has been in use in England since 1958 and in the United States since 1995.

Derived from a compound found in the French Lilac, metformin has a track record of safety and effectiveness at routine doses of up to 2,000 mg daily.4-7

So what evidence is there for the FDA to consider this drug as an anti-aging medication? The reason is simple:

Metformin can block or diminish many of the fundamental factors that accelerate aging.8-12

These include protecting against DNA damage glycation, poor mitochondrial function, and chronic inflammation. Metformin has been shown to facilitate DNA repair, which is critical for cancer prevention.

By attacking these fundamental degenerative processes, metformin can prevent the development of aging’s most troubling diseases.

Metformin has also been shown to increase the production of known longevity-promoting signaling molecules in cells, such as mTOR and AMPK—all of which reduce fat and sugar storage and increase youthful functioning at the cellular level.11,13

Studies have shown that by activating AMPK, metformin specifically impacts lifespan. For example, roundworms treated with metformin have higher AMPK activity and live about 20% longer than untreated control animals.14 Mice treated with metformin have been found to live nearly 6% longer than controls.11 And most impressively, diabetics taking metformin were shown to live 15% longer than healthy individuals without diabetes!15

AMPK activity declines with age,16 making us more vulnerable to many of the diseases associated with aging. Fortunately, a wealth of recent studies show that by activating AMPK, metformin plays a major role in preventing age-related disorders including cancer, cardiovascular disease, obesity, and neurocognitive decline.

By combatting many of the underlying causes of aging—and by activating AMPK—metformin can be considered a broad-spectrum anti-aging drug.

WHAT YOU NEED TO KNOW

Metformin as an Anti-Aging Drug

Metformin has been a staunch workhorse against diabetes for more than 50 years.

Studies show that metformin acts by boosting the activity of AMPK, a master metabolic regulator that favors fat- and sugar-burning and prevents their accumulation.

Because AMPK is relevant in all tissues, this makes metformin extremely important in reducing metabolic imbalances in the entire body.

Strong evidence suggests that metformin, through its protective effects and AMPK-activating properties, can help prevent cancer, cardiovascular disease, obesity and its consequences, and even neurodegenerative disorders.

Cancer Protective Effects of Metformin

Diabetics have an increased risk of cancer. In a study of head and neck cancers, researchers were surprised to find that diabetic patients had a 46% reduction in risk of developing these cancers compared to non-diabetic patients.17 What was the reason for this unexpected reduction? The diabetic patients were taking metformin.

Similar effects have been seen for the risk of gastric (stomach) cancers as well, with metformin users experiencing a 55% decrease in the risk of stomach cancer compared with nonusers.18 Important studies like these have helped to confirm a decade-long trend suggesting that metformin has anti-cancer properties.17

While these studies show that metformin has the potential to reduce the risk of developing cancer, others show its benefits for those who already have cancer.

A study encompassing 27 clinical trials representing more than 24,000 patients found that in people with early-stage cancers of the colon and rectum, metformin use improved recurrence-free survival by 37%, overall survival by 31%, and cancer-specific survival by 42%.19

The same study reported similar results for men with early-stage prostate cancer, with metformin use increasing recurrence-free survival by 17%, overall survival by 18%, and cancer-free survival by 42% compared with non-metformin users.19

By now, metformin has been studied in the context of total tumor incidence in 17 different target organs, 21 strains of mice, and four strains of rats. It has been studied in cancers that occur spontaneously, and in those induced by 16 different chemical carcinogens from multiple classes, ionizing radiation, viruses, genetic modifications, and high-fat diets, using five different routes of administration.20

A whopping 86% of such studies showed that metformin clearly inhibited cancer development and showed zero evidence of cancer stimulation by the drug.20

Indeed, as one expert recently put it, maybe it’s time “to make this long story short” about metformin: It works to prevent cancer.20

Metformin Prevents Cardiovascular Disease

Despite billions of dollars spent on drugs such as Crestor and Lipitor, cardiovascular disease remains the single biggest killer in America. While there are multiple causes of cardiovascular disease, most boil down to the development of atherosclerosis, or “hardening of the arteries.”

Atherosclerosis is promoted by factors such as oxidation of LDL cholesterol, accumulation of that oxidized fat in arterial walls, and damage to the endothelium, which is the thin layer of cells lining those arterial walls.21

Metformin is now known to prevent these early steps in atherosclerosis development.

One of the key ways it does this is by activating the metabolic regulator AMPK. By activating AMPK, metformin:

Mitigates LDL oxidation and the resulting endothelial dysfunction, which slows the development of atherosclerosis.21

Reduces the conversion of harmless immune system cells (monocytes) into fat-laden macrophages, an action that reduces their accumulation in vessel walls.22 It also increases cholesterol export out of those cells, while also suppressing the inflammatory stimulus they normally produce.23,24

Offers critical protection to endothelial cells that line coronary arteries, which supply blood to the heart muscle itself. Specifically, metformin enhances the resistance of endothelial cells to “fat poisoning,” the death of endothelial cells in the presence of high fat concentrations.25 This is highly protective against heart attacks, which occur when coronary arteries, blocked by atherosclerotic plaques laden with fat and inflammatory cells, fail to provide enough blood to the hard-working heart muscle.

Metformin has also been shown to prevent the fragmentation of mitochondria in endothelial cells.26 Such fragmentation is closely associated with the dysfunction of endothelial cells and is now considered an important precursor of atherosclerosis.26

The results of these protective effects have been seen in numerous human studies. In one study, heart attack patients taking metformin had a significant 75% reduction in the risk of dying after 30 days, and a 68% reduction in their risk of dying 12 months after the attack.27

Several studies have also demonstrated that metformin reduces the risk of heart attack, and is associated with reduction in stroke, atrial fibrillation (an arrhythmia), and death from all causes.28

Finally, a 2016 study showed significant reductions in systolic (top number) blood pressure in nondiabetic people taking metformin. The largest reductions were seen in those having impaired glucose tolerance or obesity.29

Obesity itself appears ready to yield to metformin treatment, as we’ll now see.

FDA APPROVES FIRST ANTI-AGING STUDY

The FDA has approved a study that will determine if metformin can do more than lower blood sugar—it will evaluate metformin’s ability to slow aging. This is the first ever anti-aging study approved by the FDA.

Studies have shown that metformin can block or diminish many of the underlying factors that accelerate aging, and it has also been shown to extend lifespan in animals. Dr. Nir Barzilai from the Albert Einstein College of Medicine, along with researchers from the American Federation for Aging Research (AFAR), want to find out if metformin can extend lifespan in humans as well.

The study, called Targeting Aging with Metformin (TAME), will evaluate 3,000 people over a course of six years. Half of the participants will receive metformin, and the other half will receive a placebo. Since aging is largely characterized by the development of disease, the success of the study will be determined by whether or not the drug delays the onset of typical age-related diseases, such as cardiovascular disease, cancer, and cognitive decline.

This groundbreaking study has the potential to change the future of how we treat disease. Developing a single drug designed to treat multiple conditions would dramatically reduce the number of drugs a typical person would need, which would reduce overall drug side effects, eliminate contraindications, and of course, save money.

None of this is good for Big Pharma’s bottom line—which is likely why no company has agreed to fund the study. Until that happens, this important study is on hold.

But you can help. AFAR is seeking individual contributions to get the TAME study started. To learn more, and make a donation if you like, visit http://www.afar.org/donate/

Metformin Reduces Body Weight and Fat Mass

Metformin’s ability to activate AMPK makes it especially beneficial in combatting obesity. This is because AMPK is a metabolic regulator that stimulates youthful cellular behaviors such as burning fat (instead of storing it), taking sugar out of the blood, and recycling cellular contents to eliminate toxic proteins.30

As a result, metformin can be expected to have important effects on body weight and fat deposits. And indeed, studies show that metformin fights obesity and reduces body fat mass, even in non-diabetic patients.

This is true in some of the most challenging populations, such as women with polycystic ovary syndrome, a major cause of obesity and endocrine problems in premenopausal women.

In one study, women with polycystic ovary syndrome were treated with 850 mg of metformin or a placebo twice daily for 6 months. During that time, those in the placebo group experienced increases in weight and blood sugar, as expected. Those taking metformin, on the other hand, had significant decreases in weight and blood sugar—with metformin-treated women losing an average of 9.24 pounds. The metformin group also had significant increases in beneficial HDL cholesterol.31

Metformin has been found to significantly reduce body weight, body mass index (BMI), and insulin resistance in patients taking modern antipsychotic medications such as olanzapine, aripiprazole, risperidone, and quetiapine.32-35 These are impressive results, since major side effects of these drugs include rapid weight gain, loss of insulin sensitivity, and other features of metabolic syndrome.36

But by far, the largest group of people fighting obesity are simply aging individuals who are otherwise healthy (nondiabetic). Metformin shows promise for this population as well.

An important study in a group of such people—all women with midlife weight gain but normal blood sugars—showed that taking metformin for 12 months reduced mean body weight by 11.6 pounds.37 In addition, treated subjects had significant decreases in their body fat percentage, a favorable change that can reduce many of the long-term consequences of obesity.

Metformin is showing promise in obese but otherwise healthy young people as well. A group of 10-16- year-olds took 2,000 mg of metformin per day or a placebo for 18 months. Those taking metformin lost nearly half a pound in fat mass. By contrast, the placebo group gained almost 4.5 pounds in fat mass.38

Metformin as Neuroprotectant

There is rapidly growing literature on metformin’s potential role in preventing neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Once again, much of this literature focuses on metformin’s ability to activate AMPK, the youth-promoting energy regulator in all of our cells.

One major effect of AMPK activation is the cleanup of accumulated misfolded proteins in brain cells. The accumulation of proteins, such as tau and beta-amyloid, contributes to brain cell death and dysfunction in neurodegenerative diseases.

Thus, it makes sense that metformin might be effective in preventing disorders associated with those proteins. Numerous animal and laboratory studies show that metformin does indeed have such effects. These studies demonstrate that metformin:

Reduces levels of an enzyme that generates beta-amyloid proteins32

Decreases the harmful effect of beta-amyloid on brain cell function39-41

Reduces levels of alpha synuclein, another protein that accumulates and causes damage in Parkinson’s disease42

Prevents the loss of dopamine-producing brain cells in a model of Parkinson’s disease43,44

Improves motor coordination in a mouse model of Parkinson’s45

In 2016, a human study showed that taking 1,000 mg of metformin twice daily for 12 months improved memory recall in a group of older adults with a condition called amnestic mild cognitive impairment (a memory-stealing predecessor of Alzheimer’s).39

Given the close connections between Alzheimer’s and diabetes (it’s been called “Type III diabetes”), there is every reason to believe that metformin, through its AMPK-activating properties, will help in the long fight to retain our minds and personalities as we age.

PRECAUTIONS AND USEFUL SUGGESTIONS WITH METFORMIN USE

Although metformin has an outstanding track record in the fight against diabetes, cancer, obesity, neurodegenerative and cardiovascular diseases, there are some precautions to be aware of with its use.

Metformin is known to interfere with the absorption of B12, increasing the risk of vitamin B12 deficiency.46,47 Low B12 levels contribute to higher concentrations of artery-clogging homocysteine—an independent risk factor for cardiovascular disease.48,49 The tiny amounts of vitamin B12 and other B-vitamins found in commercial supplements is usually not enough to offset this problem. Individuals using metformin should ensure that they are taking higher doses of B-vitamins (at least 300 mcg of methylcobalamin, the active form of vitamin B12) and checking their homocysteine levels to ensure proper protection.

Some studies have shown that metformin reduces free and total testosterone levels in men.50Testosterone is especially important in male diabetics as it enhances insulin sensitivity.51 Life Extension has previously published clinical data on the importance of maintaining youthful testosterone levels in diabetic men to improve glucose utilization.52

If a blood test shows low testosterone, applying a topical testosterone cream can restore levels of this vital hormone to youthful ranges.

Side effects associated with metformin use include gastrointestinal distress or a slight taste disturbance, usually a metallic taste. Rarely, metformin may cause a potentially serious lactic acidosis, a buildup of lactic acid in the blood.53

If you use or are considering metformin, consult your physician, take your B-vitamins, and periodically check your kidney function, homocysteine levels, and in men, free and total testosterone.

Summary

The world’s first clinical trial of a true “anti-aging” drug may be about to begin. But while the study is new, the drug is more than half a century old.

Metformin has been used for more than 50 years to treat type II diabetes. A wealth of recent studies now supports a major role for metformin in preventing age-related disorders including cancer, cardiovascular disease, obesity, and neurocognitive decline.

The American Federation for Aging Research (AFAR) has a long uphill road to get this study (called TAME, or the Targeting Aging with Metformin trial) started. They face almost-certain opposition from Big Pharma companies for whom treating—not preventing—aging is a lucrative business.

The good news is that we don’t have to wait for this new metformin study to get off the ground. Metformin is already available as a prescription medication. And many thoughtful physicians who are presented with the evidence will prescribe it based on its recognized benefits against specific age-related disorders.

There are also nutrients that have been shown to boost AMPK activity and function to lower blood glucose similar to metformin.54-57

A genomic study of baldness identified more than 200 genetic regions involved in this common but potentially embarrassing condition. These genetic variants could be used to predict a man’s chance of severe hair loss. The study, led by Saskia Hagenaars and W. David Hill of The University of Edinburgh, United Kingdom, is published February 14th, 2017 in PLOS Genetics.

Before this new study, only a handful of genes related to baldness had been identified. The University of Edinburgh scientists examined genomic and health data from over 52,000 male participants of the UK Biobank, performing a genome-wide association study of baldness. They pinpointed 287 genetic regions linked to the condition. The researchers created a formula to try and predict the chance that a person will go bald, based on the presence or absence of certain genetic markers. Accurate predictions for an individual are still some way off, but the results can help to identify sub-groups of the population for which the risk of hair loss is much higher.

The study is the largest genetic analysis of male pattern baldness to date. Many of the identified genes are related to hair structure and development. They could provide possible targets for drug development to treat baldness or related conditions.

Saskia Hagenaars, a PhD student from The University of Edinburgh’s Centre for Cognitive Ageing and Cognitive Epidemiology, who jointly led the research, said: “We identified hundreds of new genetic signals. It was interesting to find that many of the genetics signals for male pattern baldness came from the X chromosome, which men inherit from their mothers.”

Dr David Hill, who co-led the research, said: “In this study, data were collected on hair loss pattern but not age of onset; we would expect to see an even stronger genetic signal if we were able to identify those with early-onset hair loss.”

The study’s principal investigator, Dr Riccardo Marioni, from The University of Edinburgh’s Centre for Genomic and Experimental Medicine, said: “We are still a long way from making an accurate prediction for an individual’s hair loss pattern. However, these results take us one step closer. The findings pave the way for an improved understanding of the genetic causes of hair loss.”

In his excellent article series on anti-aging, anti-aging fitness expert Clarence Bass highlights this study showing that six months of progressive resistance training made the gene expression pattern of aging mitochondria appear significantly younger.

Muscles can become smaller and weaker with age (a process known as sarcopenia), and evidence suggests that a key part of the decline occurs in a component of muscle cells called the mitochondria, the primary engine of energy production.

From the study, which was done on men at an average age of 70 years old, researchers reported that “…the older individuals were able to improve strength by approximately 50%, to levels that were only 38% less than that of young individuals…”. This means that seniors engaged in weight training closed the strength gap between themselves and their counterparts who were nearly 40 years younger from 59% to 38%, which is an improvement of almost 36% in a mere six months of the study.

Muscle biopsies from the study showed “a remarkable reversal of the expression profile of 179 genes associated with age and exercise training…Genes that were down-regulated with age were correspondingly up-regulated with exercise, while genes that were up-regulated with age, were down-regulated with exercise.”

The researchers summed things up by reporting that “healthy older adults show a gene expression profile in skeletal muscle consistent with mitochondrial dysfunction and associated processes such as cell death, as compared with young individuals. Moreover, following a period of resistance exercise training in older adults, we found that age-associated transcriptome expression changes were reversed, implying a restoration of a youthful expression profile.”

So when it comes to mitochondria, weight training reversed nearly 40 years of aging!

But exercise doesn’t only affect mitochondria. Two more studies show how exercise protects DNA from the wear and tear of aging, and how the addition of fast-twitch muscle fibers precipitate fat loss and improve metabolic function – primarily by acting on telomeres.

Telomeres cap the DNA chromosomes in your cells and protect these chromosomes from damage. As you age, telomeres progressively wear and shorten from repeated cell division, oxidative stress, inflammation, and other metabolic processes, eventually leaving the cell’s chromosomes unprotected. When the caps are completely eroded or disappear, the wear and tear begins to cut into your genes, causing cells to become damaged and discarded as you grow older.

In this next study, scientists measured telomeres in twins to gauge the effect of exercise on aging, hypothesizing that “telomere dynamics might chronicle the cumulative burden of oxidative stress and inflammation and, as such, serve as an index of biological age” and that “physical activity level may have an [independent] effect on telomere attrition”.

Telomere length decreased with age. No surprises there. But both the women and men who were physically active had longer telomeres than those who were sedentary, even after adjusting for the influence of age, weight, disease, socioeconomic status, and smoking.

In addition, the study participants who spent more than 3 hours each week engaged in vigorous physical activity (such as lifting weights) had longer telomeres than subjects 10 years younger, suggesting that individuals who eschew placing a vigorous load on their body may wind up biologically older by 10 years.

Obviously, since they were studying twins, these differences weren’t due to genes, but rather due to the lifestyle factor of exercise. When one twin exercised significantly more than the other, they had longer, more durable telomeres.

In the next study, researchers found that replacing slow-twitch type I muscle fibers with stronger and faster type II muscle fibers produced a significant reduction of fat mass and insulin resistance. Endurance training develops slow-twitch fibers, but strength training builds fast-twitch fibers.

For this study, researchers used a genetically engineered mouse that contained a muscle-growth regulating gene called Akt1 that could be turned on and off by the researchers. Activating Akt1 caused the mice to grow type II fibers, without exercise (important to note, since mice don’t really lift weights that well, even when commanded to by scientists in white lab coats). When the Akt1 gene was turned on, the mice took on the characteristics of a lean and powerful sprinter or weight lifter, and when the gene was turned off, the mice reverted to a predominance of type I muscle fibers, along with becoming more obese and insulin resistant (notably, this was without an actual change in diet!).

The researchers reported that “remarkably, type II muscle growth was associated with an overall reduction in body mass, due to a large decrease in fat mass. In addition, blood tests showed that these mice became metabolically normal [with no insulin resistance]. This work shows that type 2 muscle just doesn’t allow you to pick up heavy objects, it is also important in controlling whole body metabolism. It appears that the increase in type 2 muscle fiber orchestrates changes in the body through its ability to communicate with other tissues”.

Beyond the age of 30, we lose approximately six pounds of muscle mass per decade, and these findings indicate that interventions designed to increase skeletal muscle mass (such as weight training) may prove to be critical weapons in the fight against obesity and obesity-related ailments, including diabetes, heart disease, stroke, hypertension, and cancer.

The key point here of course is that weight training, due to it’s recruitment of type II muscle fibers, appears to be more effective than cardio, endurance and aerobics for fat loss, weight control, essentially converting the cells into a fat-burning machine.

Finally, yet another study on strength training effects on telomere length in human skeletal muscle looked into reports of a phenomenon of abnormally short telomeres in skeletal muscle of athletes who had overtraining and exercise-associated fatigue. This important study looked into the question of whether long-term hard exercise might have deleterious effects on muscle telomeres. So, using muscle biopsies, the researchers compared telomere length of a group of power lifters who had trained for an average of eight years against that of a group of healthy, active subjects who had no history of strength training.

There was absolutely no abnormal shortening of telomeres in the power lifters. As a matter of fact, telomere lengths in the power lifters were significantly higher than those of the control group, and telomere length was positively correlated to the power lifters’ individual records in the squat and deadlift!

These results show for the first time that long-term weight training is not associated with an abnormal shortening of skeletal muscle telomere length, and that the heavier the load you put on your muscles, the longer your telomeres will tend to be.